• Rate of hepatotoxicity [ Designated as safety issue: Yes ]
  
• Nonrelapse mortality at day 200 [ Designated as safety issue: No ]
  
• Graft failure [ Designated as safety issue: No ]
  
• Time to engraftment [ Designated as safety issue: No ]
  
• Peak bilirubin at day 20 [ Designated as safety issue: No ]
  
• Overall survival [ Designated as safety issue: No ]
  
• Incidence and severity of graft-versus-host disease [ Designated as safety issue: No ]
  

• Progression-free survival [ Designated as safety issue: No ]
  
• Relapse rate [ Designated as safety issue: No ]
  
• Pulmonary toxicity [ Designated as safety issue: Yes ]
  

OBJECTIVES:

Primary

• Determine the incidence of hepatotoxicity, in terms of incidence of severe/moderate sinusoidal obstruction syndrome or peak bilirubin greater than 4.0 mg/dL, in patients with idiopathic myelofibrosis treated with cyclophosphamide and busulfan followed by allogeneic hematopoietic stem cell transplantation (HSCT).

Secondary

• Determine overall and nonrelapsed mortality at day 200 after HSCT in patients treated with this regimen.
• Determine peak bilirubin levels at day 20 after HSCT in patients treated with this regimen.
• Determine the incidence of pulmonary toxicity in the form of idiopathic pneumonia syndrome in patients treated with this regimen.
• Determine the rate of graft failure in patients treated with this regimen.
• Determine the time to engraftment in patients treated with this regimen.
• Determine the rate of relapse in patients treated with this regimen.
• Determine the incidence and severity of graft-versus-host disease in patients treated with this regimen.
• Evaluate the pharmacokinetics/dynamics of this regimen.
• Determine the pharmacogenomics (e.g., CYP2B6, GSTA1, Sp110) of response, toxicity, and pharmacokinetics of this regimen.

OUTLINE: This is a prospective, multicenter study.

• Conditioning and transplantation: Patients receive cyclophosphamide IV on days -7 and -6 and busulfan IV over 3 hours on days -5 to -2. Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.
• Graft-versus-host disease prophylaxis: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 200 and methotrexate IV on days 1, 3, 6, and 11.

Blood samples are obtained periodically for pharmacokinetic and pharmacogenomic studies.

After the completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of chronic idiopathic myelofibrosis OR myelofibrosis developing with polycythemia vera or essential thrombocythemia
• HLA-identical or 1-allele-mismatched related or unrelated donor of unmanipulated peripheral blood stem cells available

PATIENT CHARACTERISTICS:

• Karnofsky performance status 80-100%
• Life expectancy not limited by diseases other than myelofibrosis
• AST < 2 times upper limit of normal (ULN)
• Bilirubin ≤ 2 times ULN
• Creatinine ≤ 2 times ULN
• Creatinine clearance ≥ 50% of expected
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No HIV positivity
• No active infectious hepatitis
• No known hypersensitivity to cyclophosphamide or busulfan
• No hepatic dysfunction, such as synthetic dysfunction or cirrhosis
• No dialysis dependence

• No impaired pulmonary function, indicated by 1 of the following:

  • pO2 < 70 mm Hg and DLCO < 70% predicted
  • pO2 < 80 mm Hg and DLCO < 60% predicted
  • Receiving continuous supplementary oxygen
• No impaired cardiac function, as evidenced by ejection fraction < 35% OR active coronary artery disease

PRIOR CONCURRENT THERAPY:

• No concurrent medications known to strongly inhibit enzymes in the CYP450 pathway
• No concurrent aprepitant
• No concurrent acetylsalicylic acid or nonsteroidal anti-inflammatory drugs